The present invention is directed to a process for the debromination of 6-monobromo- and 6,6-dibromopenicillanic acid, and various derivatives thereof, by the action of a bisulfite salt. The debrominated compounds produced by the present invention find various utilities, as beta lactamase inhibitors or as intermediates in the synthesis of further useful beta-lactam compounds, as noted below.
Similar debrominations have been previously carried by the means of trialkyl- or triaryltin hydrides. For example, European Patent Application No. 0,013,617 describes the conversion of benzyl 6-beta-bromopenicillanate to benzyl penicillanate by the action of tributyltin hydride and azobisisobutyronitrile in refluxing benzene; the conversion of various esters of 6,6-dibromopenicillanate to the corresponding 6-beta-bromopenicillanate with the same reagents; the conversion of benzyl 6,6-dibromopenicillanate 1,1-dioxide to a mixture of benzyl 6-alpha- and 6-beta-bromopenicillanates with the same reagent; and conversion of benzyl or pivaloyloxymethyl 6,6-dibromopenicillanates to a mixture of the corresponding 6-alpha- and 6-beta-bromo esters by use of triphenyltin hydride in place of tributyltinhydride.
That same European Patent Application further describes the use of methyllithium at -78.degree. C., followed by acetic acid quench, for the low yield conversion of pivaloyloxymethyl 6,6-dibromopenicillanate to the corresponding 6-beta-bromo ester.
Pratt, U.S. Pat. No. 4,180,506, describes catalytic hydrogenation of 6,6-dibromopenicillanic acid over Pd/C catalyst to produce a mixture of 6-alpha- and 6-beta-bromopenicillanic acid. Clayton, J. Chem. Soc. (C), pp. 2123-2127 (1969), describes the hydrogenation of methyl 6,6-dibromopenicillanate over Pd/CaCO.sub.3 to produce methyl 6-alpha-bromopenicillanate and methyl penicillanate; and hydrogenation of 6,6-dibromopenicillanic acid over the same catalyst to produce penicillanic acid.
U.K. Patent Application No. 2,051,046 describes the conversion of 6,6-dibromopenicillanic acid salts to 6-beta-bromopenicillanic acid, and pivaloyloxymethyl 6,6-dibromopenicillanate to pivaloyloxymethyl 6-beta-bromopenicillanate, with NaBH.sub.4 or NaCNBH.sub.3 as reagent.